Opioids heal ischemic wounds in the rat

Abstract

Opioids are sometimes used to treat pain in ulcerative wounds, and it is speculated that pain interferes with the healing process. Because the direct effect of opioids on this process remains unknown, we examined the effect of topically applied opioids on the healing of open ischemic wounds in rats. Topically applied opioids hastened wound closure, particularly in the first 4 days when no healing was initiated in phosphate buffered saline solution-treated wounds. After 1 week of application, fentanyl, hydromorphone, and morphine resulted in 66%, 55%, and 42% wound closure, respectively, as compared to only 15% in control wounds. Opioid-induced healing was accompanied by a 1.5- to 2.5-fold increase in nuclear density in the granulation tissue and 45-87% increase in angiogenesis as compared to phosphate buffered saline solution-treated wounds. Fentanyl showed significantly improved healing compared to morphine and hydromorphone (p < 0.05, fentanyl vs. others). Fentanyl-induced healing was inhibited by the opioid receptor antagonist naloxone, suggesting that peripheral opioid receptor(s) mediate the healing process. Opioids accelerate healing by up-regulating both endothelial and inducible nitric oxide synthase and the vascular endothelial-derived growth factor receptor Flk1 in the wounds. We envision that opioids can be used topically to accelerate wound healing in diverse clinical conditions ranging from surgical incisions to nonhealing ischemic ulcers in pathophysiological conditions and in hospice patients.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…In ischemic wounds, locally applied opioids hastened wound closure increased granulation tissue and collagen formation, increased epidermal and dermal organization, and enhanced angiogenesis (Poonawala et al, 2005;Gross et al, 2009). The vascular endothelial-derived growth factor receptor Flk1 and nitric oxide were also up-regulated by opioids in rat (Poonawala et al, 2005) and human keratinocytes (Wolf et al, 2009).…”

“…In ischemic wounds, locally applied opioids hastened wound closure increased granulation tissue and collagen formation, increased epidermal and dermal organization, and enhanced angiogenesis (Poonawala et al, 2005;Gross et al, 2009). The vascular endothelial-derived growth factor receptor Flk1 and nitric oxide were also up-regulated by opioids in rat (Poonawala et al, 2005) and human keratinocytes (Wolf et al, 2009). However, depending on the chronicity of the wound and the stage of the healing process, some groups reported retarding effects in models of excisional wounds (Rook et al, 2008) and corneal abrasions (Sassani et al, 2003).…”

COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

“…Tumour cryosections were immunostained with the endothelial cell marker anti-CD31-PE (1 : 50 dilution; Pharmingen, San Diego, CA, USA) and the nuclear stain DAPI (Molecular Probes, Eugene, OR, USA), as described previously (Poonawala et al, 2005). Three different sections of tumour were selected for image analysis, and digital images of at least three different areas of each section were binarised and linearized to quantify total PE-positive pixels in each image as a measure of such angiogenic parameters as blood vessel length, ends and nodes, using the Image Processing Tool kit, Plug-in Functions for Adobe PhotoShop (Reindeer Games, Asheville, NC, USA), as described before .…”

“…A recently recognised peripheral effect of opioids and their receptors is the promotion of angiogenesis-dependent tumour growth. Opioids at physiologically relevant concentrations promote angiogenesis in vitro, and in breast cancer and wound healing in rodents Poonawala et al, 2005;Singleton et al, 2006). Although naloxone and naltrexone can inhibit tumour growth in rodents (Zagon and McLaughlin, 1983a;Koo et al, 1996;Gupta et al, 2002), opioid receptor antagonists cannot be used to counteract the unwanted effects of opioids without also compromising analgesia in the clinical setting.…”

“…One key mechanism of morphine-induced angiogenesis is nitric oxide (NO)-dependent MAPK phosphorylation and endothelial proliferation Poonawala et al, 2005). Morphine stimulates NO in endothelium and chronic morphine treatment increases NO synthase (NOS), NO and cyclooxygenase-2 (COX-2) in mouse kidney (Stefano et al, 1995;Arerangaiah et al, 2007).…”